Inhibition of cortico-amygdala projections underlies affective bias modification by psilocybin
Matthew D. B. Claydon, Justyna K. Hinchcliffe, Julia M. Bartlett, Caroline T. Golden, Christopher W. Thomas, Gary Gilmour, Jack R. Mellor, Bortolotto Za, Emma Robinson
bioRxiv (Cold Spring Harbor Laboratory) March 4, 2026 preprint DOI: 10.64898/2026.03.02.709133 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Translational rodent study |
|---|---|
| Population | Rats |
| Interventions | Psilocybin Psilocin |
| Duration | 24 hours after PrL infusion |
| Topics | Serotonin Psilocybin |
| Keywords | Excitatory postsynaptic potential Inhibitory postsynaptic potential Prefrontal cortex Neurotransmission Antidepressant Infralimbic cortex Postsynaptic current |
| Key points | Psilocin modulates negative affective biases by selectively suppressing excitatory input to cortico-amygdala projection neurons in the prelimbic cortex, an effect dependent on 5HT1A and 5HT2A receptor signaling and leading to sustained changes in affective bias. |
Abstract
Abstract Psilocybin, a serotonergic psychedelic, can produce rapid and enduring antidepressant effects in patients with major depressive disorder (MDD)[1, 2], yet the neural mechanisms underlying these effects remain unclear. Negative affective biases are an important neuropsychological mechanism central to the development and perpetuation of MDD[3]. Using a translational rodent model, we previously demonstrated that psilocybin modulates negative affective biases which, we hypothesize, contribute to its antidepressant effects[4]. Here, we identify the prelimbic subregion (PrL) of the rat medial prefrontal cortex (mPFC) as a key locus for the modulation of affective biases by psilocin, the active metabolite of psilocybin, and reveal a cell-type-specific bidirectional regulation of synaptic transmission. Psilocin selectively suppressed excitatory synaptic input to cortico-amygdala (CA) projection neurons, but enhanced excitatory transmission to other, putatively cortico-cortical, targets. Interestingly, suppression of the excitatory input to CA cells by psilocin, and modulation of affective biases by psilocybin, were both dependent on 5HT 1A and 5HT 2A receptor signaling. Consistent with the long-term therapeutic effects of rapidly acting antidepressants[1, 2, 4, 5], psilocin produced sustained changes to affective biases evident 24 hours after PrL infusion. In parallel, the suppressed excitatory transmission shifted to enhanced inhibitory synaptic input selectively in CA cells. Finally, chemogenetic inhibition of CA neurons in PrL recapitulated both the acute and sustained modulation of negative affective biases by psilocybin, as well as positively biasing new reward memories. Together, these findings identify modulation of the PrL cortico-amygdala circuit as a key substrate for affective bias modification by psilocybin, an effect which could explain its rapid and sustained antidepressant actions.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cites 26
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
and 21 more in the library